In Brief

Abstract

The diagnosis of Cushing's syndrome still represents a challenge in clinical endocrinology. Because untreated Cushing's syndrome is associated with significant morbidity and mortality, and because nearly all of the physical and psychologic features are reversible with curative surgical therapy, accurate diagnosis of this endocrine disorder is essential.The source of steroid excess in Cushing's syndrome is classified as either ACTH-dependent or ACTH-independent (adrenal autonomy). The former category is the most frequent (80%) and encompasses ACTH-producing pituitary (Cushing's disease) or ectopic tumors, most commonly bronchial carcinoids. Whereas Cushing's disease is four to sixfold more prevalent in women, ectopic ACTH secretion is more common in men, largely due to the higher incidence of lung cancer in males.41 Cushing's disease accounts for 70% to 80% of ACTH-dependent disease, whereas 15% to 20% is caused by ectopic sources. Adrenal tumors autonomously producing glucocorticoids are found in 20% of patients with Cushing's syndrome, and this group comprises discrete and multiple adrenal lesions, such as adenomas, carcinomas, or micronodular and macronodular hyperplasia.54Although little is known about the pathogenesis of adrenal tumors, the origin of ACTH-producing pituitary adenomas has been investigated extensively. Although the proliferation of ACTH-secreting cells was initially hypothesized to be a possible consequence of stimulation by excess hypothalamic corticotropin-releasing hormone (CRH), the monoclonal origin of most ACTH-producing pituitary tumors strongly argues against this possibility.4 Hence, it is currently believed that the acquisition of a somatic mutation leading to a growth advantage accounts for these corticotroph adenomas, but, unlike the mutations in Gsα-proteins described in many growth hormone-producing adenomas, a specific mutation has not yet been described. Rare cases of ectopic secretion of CRH resulting in the oversecretion of pituitary ACTH have been reported.2The work-up for suspected endogenous glucocorticoid excess is divided into two consecutive steps (Table 1): (1) screening and confirmatory tests for the diagnosis of clinically relevant endogenous glucocorticoid excess, and (2) the localization (differential diagnosis) of the source of hormone excess. A variety of tests have been used for the screening, diagnosis, and localization of Cushing's syndrome, each associated with specific advantages and disadvantages.20 The currently utilized tests are summarized in Table 1.